Leishmania are obligate intracellular parasites of macrophages that cause a number of disease syndromes in man. This request for a Physician Scientist Award presents a program of directed study in the areas of Biochemistry, Immunology, and Molecular Genetics, combined with a research program, to address issues of potential clinical importance regarding visceral leishmaniasis, a disease that causes significant morbidity and mortality in underdeveloped areas of the world. Directed study will occur during Phase I, which includes graduate work in Biochemistry and Microbiology Departments. Performance during this training period will be reviewed by a committee of faculty members. The research project will be initiated during Phase I and will be engaged full time during Phase II. A defense of the research proposal prior to Phase II and progress reports throughout Phase II will also be reviewed by the aforementioned faculty committee. Leishmania donovani chagasi, a cause of visceral leishmaniasis, has a biphasic life cycle. The sandfly vector acquires the parasite from a mammalian blood meal. The parasite then matures as a uniflagellated promastigote in the fly until it is reinoculated Into a mammal. After ingestion by a mononuclear phagocyte. the parasite converts to the obligate intracellular amastigote form. Cure from leishmaniasis and protection from reinfection require a parasite-specific cellular immune response. The parasite antigens which evoke a protective T cell response. and the context or route by which these antigens must be presented to cause this response, are not well-defined with the visceralizing strains of Leishmania. We propose to develop a murine model of visceral Leishmaniasis to characterize the development of cellular immunity and to test the immunogenic potential of Leishmania proteins, Including recombinant proteins from an amastigote CDNA library. Using these antigens we will address two questions: 1.Is there a difference between the antigens stimulating a response in mice that are either immune or non- immune to the parasite? and 2. Are these antigens relevant to the study of human leishmaniasis? Through our efforts, we hope to address critical questions in the immune response to this important pathogen.